Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner

Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagon...

Full description

Bibliographic Details
Main Authors:	Pajvani, Utpal B., Shawber, Carrie J., Samuel, Varman T., Birkenfeld, Andreas L., Shulman, Gerald I., Kitajewski, Jan, Accili, Domenico
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387563/

id	pubmed-3387563
recordtype	oai_dc
spelling	pubmed-33875632012-07-02 Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner Pajvani, Utpal B. Shawber, Carrie J. Samuel, Varman T. Birkenfeld, Andreas L. Shulman, Gerald I. Kitajewski, Jan Accili, Domenico Article Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagonists are in clinical testing for cancer application. Here, we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly improves insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector, Rbp-Jk. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces Glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors improves insulin sensitivity following in vivo administration in lean and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch, and suggest that Notch inhibition is beneficial to diabetes treatment, in part by helping to offset excessive FoxO1–driven hepatic glucose production. 2011-07-31 /pmc/articles/PMC3387563/ /pubmed/21804540 http://dx.doi.org/10.1038/nm.2378 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Pajvani, Utpal B. Shawber, Carrie J. Samuel, Varman T. Birkenfeld, Andreas L. Shulman, Gerald I. Kitajewski, Jan Accili, Domenico
spellingShingle	Pajvani, Utpal B. Shawber, Carrie J. Samuel, Varman T. Birkenfeld, Andreas L. Shulman, Gerald I. Kitajewski, Jan Accili, Domenico Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
author_facet	Pajvani, Utpal B. Shawber, Carrie J. Samuel, Varman T. Birkenfeld, Andreas L. Shulman, Gerald I. Kitajewski, Jan Accili, Domenico
author_sort	Pajvani, Utpal B.
title	Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
title_short	Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
title_full	Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
title_fullStr	Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
title_full_unstemmed	Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner
title_sort	inhibition of notch signaling ameliorates insulin resistance in a foxo1–dependent manner
description	Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate its function. Altered Notch signaling is seen in tumorigenesis, and Notch antagonists are in clinical testing for cancer application. Here, we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly improves insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector, Rbp-Jk. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces Glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors improves insulin sensitivity following in vivo administration in lean and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch, and suggest that Notch inhibition is beneficial to diabetes treatment, in part by helping to offset excessive FoxO1–driven hepatic glucose production.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387563/
_version_	1611540421930909696

Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1–dependent manner

Similar Items